The present invention relates to a process for the synthesis of montelukast, a pharmaceutical agent, as well as to intermediates useful in the process.
Montelukast, chemically [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, has a structure represented by formula (1):

Montelukast monosodium salt (montelukast sodium) is commonly used for treatment of asthma. It is marketed under the brand name SINGULAIR® (Merck) in the form of oral tablets, chewable tablets, and granules.
U.S. Pat. No. 5,565,473 to BELLEY et al. (see also corresponding EP 0 480 717) discloses a genus of pharmaceutically useful compounds that encompasses montelukast and salts thereof. Example 161 in connection with example 146 of U.S. Pat. No. 5,565,473 discloses the synthesis of montelukast sodium as follows:

THP as used herein means tetrahydropyranyl group, typically of the formula:
wherein the asterisk indicates a chiral carbon atom.
Many other synthetic schemes are proposed in U.S. Pat. No. 5,565,473 for making montelukast and/or other compounds. For instance, Method M of U.S. Pat. No. 5,565,473, if applied to montelukast, would appear to follow the scheme:
The S—CO bond in the compound of formula (2) would first be cleaved by hydrazine or sodium methanolate to form an —SH group and then a side chain donor, shown here for montelukast as a cyclopropane acetic acid derivative (3), would be reacted therewith to form THP-protected montelukast. W is a leaving group such as a chloro-, bromo- or mesylate group. The side chain donor reaction is carried out under the presence of a base such as cesium carbonate. The THP-protected montelukast would then be converted to montelukast in this hypothetical scheme.
Another approach has been applied in WO 95/18107. Here a crystalline alkyl- or aryl-sulfonate intermediate compound, preferably a methane sulfonate compound (iii), is reacted with a dilithium anion of 1-(mercaptomethyl)cyclopropane-1-acetic acid (iv) as represented below:

In general, the above described syntheses of montelukast comprise a reaction between a quinolinylethenylphenyl building block (e.g. compounds (i), (iii) or (2)) and a cyclopropane carboxylate building block (e.g. compounds (ii), (iv) or (3)). The above-processes, however, have various drawbacks and it would be desirable to provide a different, useful process for making montelukast and its salts, especially a process that could be performed on an industrial scale.